This project explores the cellular mechanism of action of the novel Ca2+ antagonist, Ro 40-5967 (mibefradil). The compound has answered a search that is over one decade old for a blocker of the smaller of the 2 types of Ca2+ channels found in the cardiovascular system. Up until Ro 40-5967, the low-voltage activated T-type Ca2+ channel has presented a puzzle. What is the function? The search for functions of the enigmatic transient (T)-type Ca2+ channel has taken an important first step. Characterization of the new Ca2+ antagonist, mibefradil, shows that it is a selective T-type Ca2+ channel blocker with inhibitory actions on blood vessel wall thickening. The actions of the only clinically feasible T-type Ca2+ channel blocker, mibefradil, appear to extend beyond the predicted benefits. Mibefradil advantages include vascular selectivity, freedom from negative cardiac inotropism, consistent and predictable reduction in heart rate, reduction of sub-endothelial proliferation, and vasodilator effectiveness independent of depolarization state. Mibefradil increases coronary blood flow without increasing myocardial oxygen consumption, and by decreasing heart rate and thus time spent in diastole, improves sub-endocardial and small arterial perfusion. Improved perfusion of the myocardial wall and lowered heart rate may normalize underlying pathophysiologic factors and provide long-term protection. Therefore, mibefradil is markedly different from the fast-onset, short duration Ca2+ antagonists recently under dispute, and in fact may offer an excellent solution to virtually all major flaws in presently available Ca2+ antagonists. If these hypotheses are correct, T-type Ca2+ channel block offers the promise of significant cardiovascular protective benefits in long-term treatment of hypertension and angina pectoris.